Human T-cell leukemia virus type I (HTLV-I) infects more than 25 million people world-wide. A significant percentage of infected individuals develop adult T-cell leukemia/lymphoma (ATLL) or HTLV-I-associated myelopathy (HAM/TSP). HTLV-I-associated diseases are invariably fatal with limited therapeutic options and a life expectancy of 4-6 months for acute ATL and 10 months for the lymphoma type. Projected 4-year survival rates for acute- and lymphoma-type ATL stand at 5 and 5.7%, respectively. HTLV-I is the only known transforming human retrovirus;yet the mechanisms by which the virus transforms human T-cells are still poorly understood. The genomic instability caused by the oncoprotein Tax is thought to play an important role in ATL development. Tax has been shown to constitutively activate NF-kB and stimulate cell proliferation. In addition, Tax prematurely activates the anaphase promoting complex, inhibits nucleotide excision repair and represses topoisomerase I and beta-polymerase. This project will elucidate the mechanisms employed by Tax to increase genetic instability in pre-tumoral cells and the cellular genes involved in the adaptation/tolerance of DNA damage and transformation. PUBLIC HEALTH RELEVANCE: Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus and the etiological agent of adult T-cell leukemia (ATL), an aggressive and fatal disease. Approximately 5% of HTLV-1-infected individuals will develop ATL after a long latency of 20-30 years. Therefore, it can be inferred that, in addition to HTLV-I expression, multiple cumulative genetic and epigenetic alterations in the host genome may be required for ATL. This project will elucidate the mechanism by which HTLV-1 Tax induces genetic instability and transitions from pre-tumoral to the transformed state and may lead to new treatment strategies for human cancer.